August 29, 2008

Many have wished they could take a pill or drink a potion that could “magically” keep them young and healthy. David Sinclair, an anti-aging researcher and Harvard University professor of pathology, believes he is close to producing just such a remedy.

The journey to find a proverbial fountain of youth has been years in
the making for Sinclair. He famously discovered that the chemical
resveratrol (a phytoalexin produced naturally by a variety of plants
when under attack by bacteria or fungi) extends life span in mice by up
to 24 percent and in other organisms by as much as 59 percent. Sinclair
thinks that the compounds in resveratrol may be key in bumping up the
human life span as well.

"The system at work in the mice and other organisms is
evolutionarily very old, so I suspect that what works in mice will work
in humans."

Sinclair believes that resveratrol works by activating SIRT1, a gene
that is believed by many to play a fundamental role in controlling life
span. Biologists have found that increasing the expression of SIRT1
slows aging and fends off age-related disease, including cancer and
heart disease. If resveratrol can activate SIRT1, Sinclair may indeed
have found a way to unlock the secret to a long, healthy life.

Sinclair is quite certain he’ll be successful and has found plenty
of private investors who agree with him, but some of his peers have
suggested that he doesn’t always look before he leaps. "David is
brilliant, but sometimes he is too passionate and impatient for a
scientist," says one colleague. "So far, he is fortunate that his
claims have turned out to be mostly true."

Sinclair isn’t afraid of controversial research and isn’t too
worried about what others think of him. He affectionately blames his
unconventionality on his grandmother Vera, who fled to Australia in the
wake of the failed 1956 revolution in her native Hungary.

"My grandmother is the black-sheep rebel of the family," he says.
"She gave birth to my dad at age 15 in 1939--imagine the scandal
then--and has lived with natives in New Guinea and eaten human flesh,
among other things. She once got in trouble with the police for being
the first person to wear a bikini on a Sydney beach. She's a '60s
bohemian who helped raise me and taught me how to think differently and
to question dogma."

Sinclair was attending the University of New South Wales and
studying gene regulation in yeast when he learned about longevity
research from Leonard Guarente, an MIT molecular biologist who was
visiting Australia giving lectures. At the time (1993) most people
assumed that aging was a complex and inevitable process that could not
be regulated by just a few genes. But that same year, Cynthia Kenyon, a
biologist at the University of California, San Francisco, published a
study showing how manipulating a single gene, daf2, could double the
life span of a tiny roundworm. Guarente himself was beginning
experiments on yeast that would lead to the discovery of the anti-aging
gene sir2 a couple years later.

Since the field of anti-aging was so new and unproven at the time,
Guarente only talked about it informally—as he did when a young
Australian scientist sat down next to him during lunch. "This was
incredibly serendipitous," says Sinclair. Inspired by Guarente’s
insights, he sold his Mazda Miata to buy a ticket to Boston to
interview for a postdoc position in Guarente's lab. During his
interview, he gave a spirited argument that the scientists studying
aging should look for genes that prolong life rather than genes and
mechanisms that end it. He was awarded the job.

While Sinclair was in Guarente's lab in the late 1990s, he
discovered that sir2 prevents aging in yeast by slowing down the
accumulation of ERCs, circular strands of DNA that build up in
organisms as they age, eventually killing them.

But there was still the unsolved mystery of how to modulate genes,
such as SIRT1, that regulate life span. Was there a compound that could
be taken as a pill? Companies and labs began screening thousands of
chemicals to see if one would work as a gene activator, but nothing
turned out to be very promising.

Then in February 2003 in a small shoestring lab at Harvard, Sinclair
was doing his own screening when he heard about a study suggesting that
SIRT1 was activated by certain polyphenols, including resveratrol.
Sinclair and Konrad Howitz, Biomol's director of molecular biology,
collaborated to isolate resveratrol and test it in yeast and fruit
flies. "Never in my wildest dreams did I think we would find an
activator of sir2," says Sinclair.

Their research, along with other related studies, revealed that
resveratrol-fed mice were healthier than the controls. Their cells were
also aging remarkably slowly, even though the mice were being fed a
fatty, unhealthy diet. Their research showed that mice on a high-fat
diet fed large doses of resveratrol were as healthy as mice on a
regular diet. Resveratrol also improved the mice's insulin sensitivity
and increased their energy production. In effect, the mice stayed
slender and strong regardless of a poor diet, while having
energy-charged muscles and reduced heart rate of athletes. The number
of mitochondria in their cells increased as well, which improved the
cells' overall energy output.

This success in extending the life span and improving the health and
vitality of mice partly assuaged critics who doubted resveratrol could
extend life spans in mammals. But the critics are quick to point out
that it still has to prove itself in human trials.

“Officially” Sirtris’ intention is not to produce drugs that extend
life span (since that is not a goal recognized by the FDA), but the
company has developed a supercharged version of resveratrol, called
SRT501 to treat specific age-related diseases. It has also discovered
novel small molecules that are not related to resveratrol that are
supposedly a thousand times more potent in activating the sirtuins.

"This will impact humans within a decade," says Sinclair. "That's
why I don't think there is anything more important than this quest.
That's why I take chances, and why the controversy is worth it: because
I think we are right."

Sinclair says his researchers are homing in on different sirtuin
pathways and getting “great results”. Other than that, he says he can’t
be more specific “on the record”.

The company has already started clinical trials in humans, and has
another trial planned for later this year. Will this anti-aging
visionary produce the promised results? Only time will tell, but if it
does—there will be plenty of time to tell it.

Comments

The science surrounding lifespan extension via Sir2 (Sirtuin1 in humans)has now done a 180-degree turn. The assumption was that a calorie restricted (CR) diet, the unequivocal dietary intervention that prolongs life in all life forms, upregulated Sir2 and that this could be molecularly mimicked with resveratrol, known as a red wine molecule. Later it was said this could only be done with very high doses of resveratrol and to wait for the Sirtris SRT501 drug, which was more potent. More recently, however, Leonard Guarente of MIT, Sinclair's mentor, reported that Sir2 is not universally upregulated in all organs and tissues in a calorie restricted animal, throwing question into the idea of using that gene target as a measure of potential increase lifespan. The 2003 paper in Nature magazine reporting resveratrol is a molecular mimic of calorie restriction was an in vitro test which we now realize has no bearing on live mammalian responses to CR or resveratrol. Subsequent studies have now shown lower doses of resveratrol mimic the genomic response of resveratrol, not higher doses, and when resveratrol is accompanied by other small molecules, the dosage needed to produce a genomic response similar to CR was even far lower and the genomic response 9-fold greater. Guarente also conceded that the Sir2 gene is not upregulated in CR, only that its gene-derived protein is in greater abundance because it is stabilized in a CR diet. Just less of it is degraded. Furthermore, in a followup mouse study recently reported, animals on higher and lower doses of resveratrol did not live as long as animals on a plain standard-calorie diet. So what we have here, in the last 4 years, is science which shows that it isn't Sir2/Sirtuin1 but rather any array of genes, and that lower doses of an array of small natural molecules, which can be provided in a dietary supplement, can produce a far greater genomic response. Sinclair himself now commercially touts a liquid supplement of lower-dose with accompanying polyphenolic small molecules.

As a matter of principle, I am skeptical of "free lunch" claims. Whether it's something that increases longevity without ill effects, or something that allows you to go without sleep without ill effects, or whatever -- my immediate question is: if it's that easy, why isn't nature already doing it that way?

Having said that, I have to admit there's one very singular difference between our situation now and that of pretty much every organism since the dawn of time -- we now have access to (effectively) unlimited calories, so we don't have to "decide" between healing/procreating/competing.

The suggestion that low doses of reveratrol, in the range of 100mg or less, are more efficacious than higher doses, in the range of 250mg to 500mg is counter to virtually every study and trial done on this compound since 1997. In almost all cases the researcher has noted that effects are dose dependent and the appropriate dose ranges from about 5mg/kilogram of body weight to 40mg/kilogram of body weight, or between 350mg to 2800mg daily for a 70kg person.

Combining resveratrol with other polyphenols such as curcumin, silymarin, astragulas and the antioxidants mangosteen, pomegranate, goji fruit and alpha lipoic acid has been shown to result in a synergistic array of effects far in excess of that reported for resveratrol along. The exception to this rule is quercetin, which has been clearly shown to interfere with the important metabolites of resveratol and to actually deactivate the SirT1 gene in humans.

Increasing longevity is a great thing, but we should also endeavour to try to keep Quality of Life from going down. We should endeavour to keep increasing numbers of older people in the work force, learning, etc. ( Those that are able to ) instead of in retirement homes. We're still a long way from that.

The suggestion that low doses of reveratrol, in the range of 100mg or less, are more efficacious than higher doses, in the range of 250mg to 500mg is counter to virtually every study and trial done on this compound since 1997. In almost all cases the researcher has noted that effects are dose dependent and the appropriate dose ranges from about 5mg/kilogram of body weight to 40mg/kilogram of body weight, or between 350mg to 2800mg daily for a 70kg person.

Grapes produce different forms of Resveratrol, including cis-resveratrol and trans-resveratrol. Trans-resveratrol is the type most commonly used in scientific research and trials, and EZ MELTS Resveratrol contains the purest form of trans-resveratrol available, at a 99% concentration.